Officials said on Sunday morning that the lone shooter, who was armed with an assault-type rifle, a handgun and some type of other device, died in a shootout with the police force at the Pulse nightclub.
US news networks and a Congress member have identified the gunman as a New York-born resident of Florida with Afghan origins. But investigators have yet to make an official announcement.
Florida Governor Rick Scott declared a state of emergency following the shooting.
Ron Hopper, of the US Federal Bureau of Investigation, said authorities would not yet release the name of the shooter to avoid jeopardising the investigation. He added that it is too early to say if the incident is linked to "terrorism or hate crime".
Orlando Police chief John Mina described the shooting as "one of the worst tragedies we have seen", adding that police officers "were shaken by what they have seen inside the club".
The injured, "many critically ill", had been transferred to nearby hospitals, police and medical officials said. Among those injured was one police officer, whose kevlar helmet was hit by a round from the suspect.
"This did turn into a hostage situation. At approximately 05:00 hours (09:00 GMT) this morning, the decision was made to rescue hostages that were in there," Mina said in an earlier press conference on Sunday.
In a statement, the White House press office said US President Barack Obama was briefed of the incident by Lisa Monaco, top adviser for Homeland Security and Counterterrorism.
As the shooting occurred, the nightclub urged patrons to "get out" and "keep running" in a post on its Facebook page.
One witness, who said he was inside the building during the incident, said that he heard about 40 shots being fired.
Police said they carried out a "controlled explosion" at the club hours after the shooting broke out, while entering the nightclub.
Video posted online showed a large number of police and emergency vehicles outside the nightclub, following the shooting.
The nightclub shooting came just a day after a man thought to be a deranged fan fatally shot Christina Grimmie, a rising singing star who gained fame on YouTube and as a contestant on The Voice, while she was signing autographs after a concert in Orlando.[Konfr]
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